CA2632807A1 - Inhibitors of iap - Google Patents
Inhibitors of iap Download PDFInfo
- Publication number
- CA2632807A1 CA2632807A1 CA002632807A CA2632807A CA2632807A1 CA 2632807 A1 CA2632807 A1 CA 2632807A1 CA 002632807 A CA002632807 A CA 002632807A CA 2632807 A CA2632807 A CA 2632807A CA 2632807 A1 CA2632807 A1 CA 2632807A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- heterocycle
- compound
- carbocycle
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 149
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- -1 amino, cyano nitro, amidino, guanidino Chemical group 0.000 claims description 235
- 125000000217 alkyl group Chemical group 0.000 claims description 123
- 125000000623 heterocyclic group Chemical group 0.000 claims description 100
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 74
- 229910052736 halogen Inorganic materials 0.000 claims description 53
- 150000002367 halogens Chemical class 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 52
- 125000003545 alkoxy group Chemical group 0.000 claims description 44
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 43
- 125000002252 acyl group Chemical group 0.000 claims description 41
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 230000006907 apoptotic process Effects 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 102000011727 Caspases Human genes 0.000 claims description 20
- 108010076667 Caspases Proteins 0.000 claims description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
- 125000004043 oxo group Chemical group O=* 0.000 claims description 20
- 125000001188 haloalkyl group Chemical group 0.000 claims description 19
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 17
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 230000005855 radiation Effects 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 230000027455 binding Effects 0.000 claims description 11
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 11
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 11
- 108091007065 BIRCs Proteins 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- 230000001640 apoptogenic effect Effects 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000005884 carbocyclylalkyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 241001061127 Thione Species 0.000 claims description 5
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 5
- 229960004679 doxorubicin Drugs 0.000 claims description 5
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 5
- 230000001939 inductive effect Effects 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 230000001235 sensitizing effect Effects 0.000 claims description 5
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 229940009456 adriamycin Drugs 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 3
- 229960004316 cisplatin Drugs 0.000 claims description 3
- 230000002018 overexpression Effects 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 3
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 claims description 2
- VTBOTOBFGSVRMA-UHFFFAOYSA-N 1-Methylcyclohexanol Chemical compound CC1(O)CCCCC1 VTBOTOBFGSVRMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- HCFRWBBJISAZNK-UHFFFAOYSA-N 4-Hydroxycyclohexylcarboxylic acid Chemical compound OC1CCC(C(O)=O)CC1 HCFRWBBJISAZNK-UHFFFAOYSA-N 0.000 claims description 2
- 108010006654 Bleomycin Proteins 0.000 claims description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 2
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 2
- 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 2
- 229960001561 bleomycin Drugs 0.000 claims description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
- 229940127093 camptothecin Drugs 0.000 claims description 2
- 229960001338 colchicine Drugs 0.000 claims description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 2
- 229960004397 cyclophosphamide Drugs 0.000 claims description 2
- 229960000684 cytarabine Drugs 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 2
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 claims description 2
- 229960004039 finasteride Drugs 0.000 claims description 2
- 229960000390 fludarabine Drugs 0.000 claims description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 2
- 229960005277 gemcitabine Drugs 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 229960004857 mitomycin Drugs 0.000 claims description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 2
- 229960001156 mitoxantrone Drugs 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- 229960001603 tamoxifen Drugs 0.000 claims description 2
- 229940063683 taxotere Drugs 0.000 claims description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 2
- 229960000303 topotecan Drugs 0.000 claims description 2
- 229960003048 vinblastine Drugs 0.000 claims description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 2
- 229960004528 vincristine Drugs 0.000 claims description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 2
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical group C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 230000036210 malignancy Effects 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 65
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- 239000000203 mixture Substances 0.000 description 55
- 235000019439 ethyl acetate Nutrition 0.000 description 53
- 229910001868 water Inorganic materials 0.000 description 53
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 39
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 27
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 125000001424 substituent group Chemical group 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- 229910000027 potassium carbonate Inorganic materials 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 21
- 239000000523 sample Substances 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 19
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 230000002829 reductive effect Effects 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 125000006239 protecting group Chemical group 0.000 description 17
- 108090000623 proteins and genes Proteins 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 102000004169 proteins and genes Human genes 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 235000018102 proteins Nutrition 0.000 description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- 125000001072 heteroaryl group Chemical group 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 13
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 11
- 201000009030 Carcinoma Diseases 0.000 description 10
- 229910004373 HOAc Inorganic materials 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 10
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 10
- 125000006304 2-iodophenyl group Chemical group [H]C1=C([H])C(I)=C(*)C([H])=C1[H] 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 102100033189 Diablo IAP-binding mitochondrial protein Human genes 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 108010049207 Death Domain Receptors Proteins 0.000 description 8
- 102000009058 Death Domain Receptors Human genes 0.000 description 8
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
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- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Steroid Compounds (AREA)
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| KR20120127754A (ko) | 2004-12-20 | 2012-11-23 | 제넨테크, 인크. | Ｉａｐ의 피롤리딘 억제제 |
| PL1851200T3 (pl) | 2005-02-25 | 2014-06-30 | Tetralogic Pharm Corp | Dimeryczne inhibitory IAP |
| US7772177B2 (en) | 2005-05-18 | 2010-08-10 | Aegera Therapeutics, Inc. | BIR domain binding compounds |
| WO2007048224A1 (en) | 2005-10-25 | 2007-05-03 | Aegera Therapeutics Inc. | Iap bir domain binding compounds |
| AU2006340014B2 (en) | 2005-12-19 | 2012-12-20 | Genentech, Inc. | Inhibitors of IAP |
| TWI543988B (zh) | 2006-03-16 | 2016-08-01 | 科學製藥股份有限公司 | 結合於細胞凋亡抑制蛋白（ｉａｐ）之桿狀病毒ｉａｐ重複序列（ｂｉｒ）區域之化合物 |
| AU2007250443B2 (en) | 2006-05-16 | 2013-06-13 | Pharmascience Inc. | IAP BIR domain binding compounds |
| WO2008014263A2 (en) | 2006-07-24 | 2008-01-31 | Tetralogic Pharmaceuticals Corporation | Dimeric iap antagonists |
| EP2049524A2 (en) * | 2006-07-24 | 2009-04-22 | Tetralogic Pharmaceuticals Corporation | Iap inhibitors |
| WO2008014229A2 (en) * | 2006-07-24 | 2008-01-31 | Tetralogic Pharmaceuticals Corporation | Dimeric iap inhibitors |
| CA2666112A1 (en) * | 2006-10-12 | 2008-04-17 | Novartis Ag | Pyrrolydine derivatives as iap inhibitors |
| US20100055071A1 (en) * | 2006-11-21 | 2010-03-04 | Martin Robert Leivers | Anti-Viral Compounds |
| EP2125809A1 (en) * | 2006-12-19 | 2009-12-02 | Genentech, Inc. | Imidazopyridine inhibitors of iap |
| CL2008001234A1 (es) * | 2007-04-30 | 2008-09-22 | Genentech Inc | Compuestos derivados de heterociclos nitrogenados, inhibidores de las proteinas de apoptosis; y uso en el tratamiento del cancer. |
| EP2156189A1 (en) * | 2007-05-07 | 2010-02-24 | Tetralogic Pharmaceuticals Corp. | Tnf gene expression as a biomarker of sensitivity to antagonists of inhibitor of apoptosis proteins |
| KR20100110870A (ko) * | 2008-01-11 | 2010-10-13 | 제넨테크, 인크. | Ｉａｐ의 억제제 |
| EP2303841A1 (en) | 2008-07-14 | 2011-04-06 | Gilead Sciences, Inc. | Oxindolyl inhibitor compounds |
| AU2009279924B2 (en) | 2008-08-02 | 2014-10-02 | Genentech, Inc. | Inhibitors of IAP |
| NZ590500A (en) * | 2008-08-16 | 2012-06-29 | Genentech Inc | Azaindole inhibitors of iap |
| KR20120031170A (ko) | 2009-06-08 | 2012-03-30 | 길리애드 사이언시즈, 인코포레이티드 | 알카노일아미노 벤즈아미드 아닐린 ｈｄａｃ 저해제 화합물 |
| US8283357B2 (en) | 2009-06-08 | 2012-10-09 | Gilead Sciences, Inc. | Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds |
| US8283372B2 (en) | 2009-07-02 | 2012-10-09 | Tetralogic Pharmaceuticals Corp. | 2-(1H-indol-3-ylmethyl)-pyrrolidine dimer as a SMAC mimetic |
| WO2011016576A1 (en) | 2009-08-04 | 2011-02-10 | Takeda Pharmaceutical Company Limited | Alanine derivatives as inhibitors of apoptosis proteins |
| US8362068B2 (en) * | 2009-12-18 | 2013-01-29 | Idenix Pharmaceuticals, Inc. | 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors |
| NZ602368A (en) | 2010-02-12 | 2014-10-31 | Pharmascience Inc | Iap bir domain binding compounds |
| GB201106817D0 (en) | 2011-04-21 | 2011-06-01 | Astex Therapeutics Ltd | New compound |
| WO2015091584A1 (en) * | 2013-12-18 | 2015-06-25 | F. Hoffmann-La Roche Ag | Thiazolopyridine compounds, compositions and their use as tyk2 kinase inhibitors |
| CN105829310B (zh) | 2013-12-20 | 2019-04-12 | 阿斯特克斯治疗有限公司 | 双环杂环化合物及其治疗用途 |
| CN105585583B (zh) * | 2016-01-20 | 2018-04-13 | 广东工业大学 | 一种非肽类凋亡抑制蛋白拮抗剂及其合成方法与应用 |
| CN105566447B (zh) * | 2016-01-20 | 2019-09-20 | 广东工业大学 | 一种凋亡抑制蛋白的类肽拮抗剂及其合成方法与应用 |
| CN106188098B (zh) * | 2016-07-06 | 2017-11-03 | 广东工业大学 | 一种杂化抗癌药物及其制备方法与应用 |
| JP7515175B2 (ja) | 2018-07-31 | 2024-07-12 | ファイメクス株式会社 | 複素環化合物 |
| WO2021020585A1 (ja) | 2019-07-31 | 2021-02-04 | ファイメクス株式会社 | 複素環化合物 |
| AU2021211871A1 (en) | 2020-01-20 | 2022-09-08 | Astrazeneca Ab | Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
| CN113402464A (zh) * | 2021-03-15 | 2021-09-17 | 深圳市谦陌通辰实验有限公司 | 一种基于铃木反应的氟唑菌酰胺的合成方法 |
| CN113149908A (zh) * | 2021-04-08 | 2021-07-23 | 深圳市雁程化工有限公司 | 一种基于铃木反应的联苯吡菌胺的合成方法 |
| CA3234317A1 (en) | 2021-10-22 | 2023-12-14 | Wa Xian | Methods and compositions for treating chronic inflammatory injury, metaplasia, dysplasia and cancers of epithelial tissues |
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| FR2575753B1 (fr) * | 1985-01-07 | 1987-02-20 | Adir | Nouveaux derives peptidiques a structure polycyclique azotee, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| DE3685626T2 (de) * | 1985-09-26 | 1993-01-28 | Beckmann Research Inst Of The | Sequenzierung von peptiden. |
| IT1226100B (it) * | 1988-07-07 | 1990-12-10 | Dompe Farmaceutici Spa | Derivati benzimidazolici farmacologicamente attivi. |
| US4935494A (en) * | 1988-11-15 | 1990-06-19 | City Of Hope | C-terminal peptide and protein sequencing |
| DK167813B1 (da) * | 1989-12-07 | 1993-12-20 | Carlbiotech Ltd As | Pentapeptidderivat, farmaceutisk acceptable salte heraf, fremgangsmaade til fremstilling deraf og farmaceutisk praeparat indeholdende et saadant derivat |
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-
2006
- 2006-12-19 AU AU2006340014A patent/AU2006340014B2/en not_active Expired - Fee Related
- 2006-12-19 EP EP06850324A patent/EP1973899A4/en not_active Withdrawn
- 2006-12-19 US US12/096,590 patent/US8247557B2/en not_active Expired - Fee Related
- 2006-12-19 KR KR1020087017641A patent/KR20080080203A/ko not_active Ceased
- 2006-12-19 RU RU2008129683/04A patent/RU2451025C2/ru not_active IP Right Cessation
- 2006-12-19 CA CA002632807A patent/CA2632807A1/en not_active Abandoned
- 2006-12-19 CN CNA2006800530088A patent/CN101374829A/zh active Pending
- 2006-12-19 JP JP2008547736A patent/JP5155184B2/ja not_active Expired - Fee Related
- 2006-12-19 NZ NZ594746A patent/NZ594746A/xx not_active IP Right Cessation
- 2006-12-19 WO PCT/US2006/062335 patent/WO2007106192A2/en not_active Ceased
-
2008
- 2008-06-05 IL IL191997A patent/IL191997A0/en unknown
- 2008-06-12 ZA ZA2008/05152A patent/ZA200805152B/en unknown
- 2008-07-18 NO NO20083207A patent/NO20083207L/no not_active Application Discontinuation
-
2012
- 2012-07-05 US US13/542,548 patent/US20120270886A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CN101374829A (zh) | 2009-02-25 |
| WO2007106192A2 (en) | 2007-09-20 |
| WO2007106192A3 (en) | 2008-04-24 |
| KR20080080203A (ko) | 2008-09-02 |
| JP2009520041A (ja) | 2009-05-21 |
| US20120270886A1 (en) | 2012-10-25 |
| NZ594746A (en) | 2013-03-28 |
| US20090221630A1 (en) | 2009-09-03 |
| RU2008129683A (ru) | 2010-01-27 |
| RU2451025C2 (ru) | 2012-05-20 |
| EP1973899A4 (en) | 2010-10-20 |
| AU2006340014B2 (en) | 2012-12-20 |
| AU2006340014A1 (en) | 2007-09-20 |
| ZA200805152B (en) | 2009-12-30 |
| IL191997A0 (en) | 2008-12-29 |
| NO20083207L (no) | 2008-09-17 |
| US8247557B2 (en) | 2012-08-21 |
| EP1973899A2 (en) | 2008-10-01 |
| JP5155184B2 (ja) | 2013-02-27 |
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| FZDE | Discontinued |
Effective date: 20140722 |